The potential roles of gene and chromosomal mutations, as well as transposition and altered expression of normal genes, during the complex carcinogenic process has been supported by some recent dramatic experiments. In experimental carcinogenesis, as well as epidemiological cancer studies, the initiation/promotion model appears to be able, in many cases, to explain the multistage nature of carcinogenesis. This project proposes to continue basic studies on the mechanisms of mutagenesis in mammalian cells and how mutations might relate to the mechanism of carcinogenic initiation. In addition, studies on the mechanisms of gap junction-mediated intercellular communication in mammalian cells will be continued. To achieve these two major goals, genetic mutants affecting DNA repair and DNA replication enzymes will be isolated and characterized, genetically. Using hyperthermia to inhibit DNA polymerase Beta, aphidicolin to inhibit DNA polymerase Alpha and 3-aminobenzamide to inhibit ADP-(ribosyl)-polymerase, the roles of these enzymes in DNA replication, repair, cytotoxicity, endoreduplication and mutagenesis will be studied in Chinese hamster and human cells in vitro. Mutants affecting metabolic cooperation will be used to study the potential role of gap junctions in modulating gene expression. In addition, in vitro and in vivo studies on correlating the ability of cells from human tumors to metabolically cooperative with their ability to grow in nude mice will be performed. Lastly, recombinant DNA techniques will be used to test the hypothesis that the sarc gene, which can transform NIH-3T3 cells, does so by interfering with gap junction-mediated intercellular communication.